Factors affecting the sensitivity of the cholinergically innervated target organs, particularly the iris sphincter and the ciliary muscle of the mammalian eye to their agonists, and the mechanisms involved in the such alterations in target organ sensitivity will be studied. Subsensitivity to the miotic (and ocular hypotensive) effect of cholinomimetics will be induced by the use of chronic cholinesterase inhibitor treatment, exposure to continuous light, or by frequent application of the cholinomimetics themselves. Supersensitivity will be induced by intravitreal hemicholinium injections, stimulus deprivation (continuous darkness), ciliary ganglionectomy or retrobulbar injection of ethyl alcohol. Alteration in the sensitivity of the ciliary muscle to cholinomimetics will be studied by measuring IOP, and/or outflow facility in primates that have a scleral spur or by measuring accommodation. The specificity of the induced changes in sensitivity will be checked by studying the sensitivity of these muscles to other agents, such as prostaglandins (PGs), which also have a miotic and IOP lowering effect on the eye. The possibility of experimentally manipulating the sensitivity of the eye to the IOP lowering effects of PGs themselves will be investigated. With respect to the mechanism of alteration of cholinergic sensitivity, we will study changes in the concentration of cholinergic receptors and their affinity for cholinergic agonists by the 3H QNB method. The possible involvement of the PG system in the control of cholinergic sensitivity will be investigated by modifying the availability of natural PGs and studying the effects of PG analogs on the time course of development of subsensitivity and supersensitivity to miotics. The possible involvement of the cyclic AMP system in modifying target organ sensitivity will be checked by determining the cyclic AMP concentration and the adenyl cyclase activity of normal, subsensitive and supersensitive intraocular muscles.